Cytomegalovirus (CMV) is the most common recognized cause of viral-induced psychomotor retardation. Because infants with congenital infection continue to shed CMV for several years and may have ongoing tissue destruction despite the presence of humoral immunity to the virus, we postulated that a defect in CMV-specific cell-mediated immunity might be responsible for failure to clear virus from infected organs. We have now demonstrated, using a lymphocyte proliferation assay which we developed, a CMV-specific cell-mediated immune defect in 4 young children with active CMV infections. Our findings have recently been confirmed by another group. Thus, it is possible that a CMV-specific cell-mediated defect is responsible for the clinical manifestations and this prompts our proposal. We plan an intensive epidemiologic, virologic and immunologic investigation of the role of CMV-specific cell-mediated immunity in the pathogenesis of congenital CMV. Adults who have primary CMV mononucleosis will be studied to establish the kinetics of CMV-specific humoral and cell-mediated immunity in normal hosts. Infants from newborn nurseries will be screened to detect asymptomatic CMV infections, and those infected will have CMV-specific immune studies performed. Normal pregnant women will be studied to establish the effect of pregnancy on CMV-specific cell-mediated immunity. Infants with clinical manifestations of congenital CMV will be studied for at least 3 years. These patients will be randomized into 3 groups to receive under a double-blind protocol either transfer factor from donors whose in vitro lymphocyte proliferation to CMV is positive, transfer factor from donors who lack humoral and cell-mediated immunity to CMV or placebo. This study should delineate the role of CMV-specific cell-mediated immunity in the pathogenesis of congenital CMV, and determine if transfer factor is beneficial for congenital CMV.